AT BEDSIDE
Adverse effects of the consumption of artificial sweeteners –
systematic review
Efeitos adversos do consumo de adoçantes artificiais – revisão sistemática
Bernardo WM1, Simões RS1, Buzzini RF1, Nunes VM1, Glina FPA1
1
Guidelines Project, Associação Médica Brasileira
Objective
Guide health professionals and the general public about the
use of artificial sweeteners and their consequences for health.
Methodology
Inclusion and exclusion criteria
Studies that evaluated adults and children who used ar-
tificial sweeteners compared with individuals who did not
were included. As outcome, the adverse clinical effects of
this association were analyzed.
Exclusion criteria were non-epidemiological and non-
comparative studies, and those in disagreement with the
inclusion criteria.
Databases
The following databases and respective searches were used.
•• Medline/PubMed: (Sweetening Agents/adverse ef-
fects OR Saccharin OR Cyclamate* OR Aspartame
OR Acetosulfame OR Acesulfame) AND (Risk Fac-
tors OR Risk OR Risk Assessment OR Neoplasm* OR
Carcinoma OR Cancer OR Carcinogenic) AND (Etio-
logy/Broad[filter] OR Prognosis/Broad[filter] OR
Comparative study OR Comparative studies).
•• Embase: ‘saccharin’/exp OR saccharin OR cyclama-
te* OR ‘aspartame’/exp OR aspartame OR acetosul-
fame OR ‘acesulfame’/exp OR acesulfame AND (‘risk’/
exp OR risk AND factors OR ‘risk’/exp OR risk AND
assessment OR neoplasm* OR ‘carcinoma’/exp OR
carcinoma OR ‘cancer’/exp OR cancer OR carcinoge-
nic) AND (‘controlled study’/de OR ‘human’/de).
•• Cochrane Library: ‘(Sweetening Agents OR Saccha-
rin OR Cyclamate OR Aspartame OR Acetosulfame
OR Acesulfame) in title abstract keywords in Trials’.
•• Lilacs/Scielo: (Sweetening Agents OR Saccharin OR
Cyclamate OR Aspartame OR Acetosulfame OR Ace-
sulfame).
Critical assessment
The evidence retrieved was selected from critical evaluation1,2
(D) using as discriminatory instrument (score) the New
120
Bernardo WM et al.
http://dx.doi.org/10.1590/1806-9282.62.02.120
Castle Ottawa Scale3(D) for observational studies. After
defining the potential studies, these were classified by
strength of evidence and grade of recommendation ac-
cording to the Oxford classification,4(D) including the
strongest evidence available.
Results
453 articles were retrieved from Medline, 523 from Em-
base, 510 from Cochrane Library, and 99 from Lilacs/Sci-
elo. 40 articles were selected by reading the title and ab-
stract. After reading the full text, 14 studies were selected.
Analysis
Pregnant women
A study including 59.334 pregnant women evaluated the
association between intake of artificially-sweetened or
sucrose-sweetened soft drinks, carbonated or not, and
the birth of preterm (< 37 weeks) infants as the primary
endpoint. This association was confirmed with p ≤ 0.001
for both variables. In the comparison with pregnant
women who did not consume sweetened soft drinks, the
adjusted odds ratio (OR) for the women consuming one
or more units of sweetened carbonated soft drink per
day was 1.38 (95CI = 1.15 - 1.65); for those consuming ≥
4 units/day, the OR was 1.78 (95CI = 1.19 - 2.66). 5(B) Re-
inforcing these data, a study linked the high intake of
artificially-sweetened drinks with prematurity; the ad-
justed OR for those who drank > 1 serving/day was 1.11
(95CI = 1.00 - 1.24).6(B)
Another group of pregnant women (60,466) was eval-
uated for intake during pregnancy of artificially-sweetened
drinks in relation to childhood asthma and allergic rhini-
tis. In 18 months, it was found that mothers who con-
sumed more artificially-sweetened noncarbonated drinks
were more likely (OR = 1.23; 95CI = 1.13 to 1.33) to report
a diagnosis of asthma in their children, compared to con-
sumers of sugar-sweetened beverages. Similarly, mothers
who consumed artificially-sweetened carbonated drinks
had a greater chance of having a child diagnosed with asth-
ma at age 7 (OR = 1.30; 95CI = 1.01 - 1.66), which was not
Rev Assoc Med Bras 2016; 62(2):120-122
Adverse effects of the consumption of artificial sweeteners – systematic review
found for self-reported allergic rhinitis (OR = 1.31; 95CI =
0.98 - 1.74). These associations were not found with the
use of sugar-sweetened beverages.7(B)
Type 2 diabetes
To evaluate the association of type 2 diabetes (T2D) with
intake of sugar-sweetened or artificially-sweetened drinks,
a study included healthy men (n = 40.389) and found
2,680 cases of type 2 diabetes within 20 years. Artificial-
ly-sweetened drinks were not associated with T2D, after
multivariate analysis (adjusted) [HR = 1.09; 95CI = 0.98 -
1.21; p = 0.13).8(B)
Cancer
In order to evaluate the relationship between the con-
sumption of aspartame and the incidence of hematopoi-
etic cancer and brain cancer, a study selected 340,045 men
and 226,945 women. After excluding other participants
(n = 473.984), the population was followed for 5 years,
with histological confirmation for hematopoietic cancers
(n = 1888) and brain cancers (n = 315). There was no as-
sociation between the intake of high levels of aspartame
and risk of hematopoietic cancer (RR for ≥ 600 mg/day =
0.98; 95CI = 0.76 - 1.27), glioma (RR for ≥ 400 mg/day =
0.73; 95CI = 0.46 - 1.15; p = 0.05 [inverse linear trend]), or
their subtypes in both men and women.10(B)
Another epidemiological study included two cohorts
to prospectively evaluate if the consumption of soft drinks
containing aspartame or sugar is associated with the risk
of hematopoietic cancers. When the data for males and
females from both cohorts were combined, there was an
increased risk of leukemia for consumption ≥ 1 unit of
diet soda per day (RR = 1.42; 95CI = 1.00 - 2.02).9(B)
Chance cannot be excluded from these results due to the
inconsistent effect of gender.11(B)
Assessing the maternal consumption of aspartame
during pregnancy or breastfeeding, the risk of brain tu-
mor was investigated. 56 cases of brain tumor in children
and 94 controls matched for age and gender were evalu-
ated. There was no association between aspartame con-
sumption by both the mother and the child and the risk
of brain tumor development (OR with 95CI containing
the unit for all comparisons).12(B) A second study, which
included 315 mothers of children with medulloblastoma
diagnosed before 6 years of age and 315 mothers of con-
trol children, also found no association between aspar-
tame consumption during pregnancy and the risk of brain
tumor.13(B) There is no association between glioma and
aspartame consumption in adults.10(B)
Rev Assoc Med Bras 2016; 62(2):120-122
Data from extensive investigations on the possibility
of neurotoxic effects of aspartame, in general, do not sup-
port the hypothesis that aspartame in the human diet will
affect nervous system function, learning and behavior.14(A)
An Italian study, including as cases patients hospi-
talized for various types of cancers and as controls (n =
7,028) patients with hospitalization for non-neoplastic
acute illness, compared the association between con-
sumption of sugar or artificial sweeteners, especially as-
partame, and the development neoplasms. There was no
association between the use of artificial sweeteners and
cancer of the oral cavity, pharynx, esophagus, stomach,
colon, rectum, endometrium and prostate. Regarding
ovarian tumor, only the use of saccharin decreased the
chance of occurrence.15,16(B)
Evaluating the association between consumption of
sugar and other artificial sweeteners, particularly aspar-
tame, there was no relationship with the development of
kidney tumor. For sugar, the adjusted OR was 0.79 (95CI
= 0.49 – 1.28) and for other sweeteners, especially aspar-
tame, the adjusted OR was 1.03 (95CI = 0.73 - 1.46).15(B)
In humans, a study of 7655 cases showed no associ-
ation between the consumption of artificial sweeteners
and bladder cancer (RR = 0.97; 95CI = 0.92 - 1.04).17(B)
Infertility
Including 405 cases of clinically-defined infertility (30 -
50 years) and 379 controls, the relation between cycla-
mate or its metabolite cyclohexylamine and male fertili-
ty was assessed. No evidence was found of a significant
association between the consumption of cyclamate and
male infertility.18(B)
Evidence summary
1. Daily consumption of artificially-sweetened soft drinks
by pregnant women can increase the likelihood of pre-
maturity.
2. The consumption of artificially-sweetened drinks by
pregnant women may be associated with the diagno-
sis of asthma in their children up to the age of 7 years.
3. There is no association between aspartame consump-
tion during pregnancy, lactation or by the child and
brain tumor in childhood and adulthood.
4. There is no association between aspartame consump-
tion and risk of hematopoietic cancer.
5. There is no association between the consumption of
sugar or other sweeteners, particularly aspartame, and
the development of cancer in the digestive and repro-
ductive systems.
121

6. Consumption of artificial sweeteners is not associated
with the development of kidney or bladder cancer in
humans.
7. The association between intake of artificially-sweete-
ned drinks and type 2 diabetes is uncertain.
8. There is no association between the consumption of
cyclamate and male infertility.
References
1. Nobre MR, Bernardo WM, Jatene FB. A prática clínica baseada em evidências.
Parte I – Questões clínicas bem construídas. Rev Assoc Med Bras. 2003;
49(4):445-9.
2. Bernardo WM, Nobre MR, JateneFB. A prática clínica baseada em evidências.
Parte II – Questões clínicas bem construídas. Rev Assoc Med Bras. 2004;
50(1):104-8.
3. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The
Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized
studies in meta-analyses. Available from: http://www.ohri.ca/programs/
clinical_epidemiology/oxford.asp
4. Levels of Evidence and Grades of Recommendations - Oxford Centre for
Evidence-Based Medicine. Available from: www.cebm.net.
5. Halldorsson TI, Strøm M, Petersen SB, Olsen SF. Intake of artificially sweetened
soft drinks and risk of preterm delivery: a prospective cohort study in 59,334
Danish pregnant women. Am J Clin Nutr. 2010; 92(3):626-33.
6. Englund-Ögge L, Brantsæter AL, Haugen M, Sengpiel V, Khatibi A, Myhre
R, et al. Association between intake of artificially sweetened and sugar-
sweetened beverages and preterm delivery: a large prospective cohort study.
Am J Clin Nutr. 2012; 96(3):552-9.
7. Maslova E, Strøm M, Olsen SF, Halldorsson TI. Consumption of artificially-
sweetened soft drinks in pregnancy and risk of child asthma and allergic
rhinitis. PLoS One. 2013; 8(2):e57261.
8. de Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-sweetened and
artificially sweetened beverage consumption and risk of type 2 diabetes in
men. Am J Clin Nutr. 2011; 93(6):1321-7.
122
Bernardo WM et al.
9. Fagherazzi G, Vilier A, Saes Sartorelli D, Lajous M, Balkau B, Clavel-Chapelon
F. Consumption of artificially and sugar-sweetened beverages and incident
type 2 diabetes in the Étude Épidémiologique auprès des femmes de la
Mutuelle Générale de l’Education Nationale – European Prospective
Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2013;
97(3):517-23.
10. Lim U, Subar AF, Mouw T, Hartge P, Morton LM, Stolzenberg-Solomon R,
et al. Consumption of aspartame-containing beverages and incidence of
hematopoietic and brain malignancies. Cancer Epidemiol Biomarkers Prev.
2006; 15(9):1654-9.
11. Schernhammer ES, Bertrand KA, Birmann BM, Sampson L, Willett WC,
Feskanich D. Consumption of artificial sweetener- and sugar-containing
soda and risk of lymphoma and leukemia in men and women. Am J Clin
Nutr. 2012; 96(6):1419-28.
12. Gurney JG, Pogoda JM, Holly EA, Hecht SS, Preston-Martin S. Aspartame
consumption in relation to childhood brain tumor risk: results from a case-
control study. J Natl Cancer Inst. 1997; 89(14):1072-4.
13. Bunin GR, Kushi LH, Gallagher PR, Rorke-Adams LB, McBride ML, Cnaan
A. Maternal diet during pregnancy and its association with medulloblastoma
in children: a children’s oncology group study (United States). Cancer Causes
Control. 2005; 16(7):877-91.
14. Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, et
al. Aspartame: a safety evaluation based on current use levels, regulations,
and toxicological and epidemiological studies. Crit Rev Toxicol. 2007;
37(8):629-727.
15. Gallus S, Scotti L, Negri E, Talamini R, Franceschi S, Montella M, et al.
Artificial sweeteners and cancer risk in a network of case-control studies.
Ann Oncol. 2007; 18(1):40-4.
16. Bosetti C, Gallus S, Talamini R, Montella M, Franceschi S, Negri E, et al.
Artificial sweeteners and the risk of gastric, pancreatic, and endometrial
cancers in Italy. Cancer Epidemiol Biomarkers Prev. 2009; 18(8):2235-8.
17. Elcock M, Morgan RW. Update on artificial sweeteners and bladder cancer.
Regul Toxicol Pharmacol. 1993; 17(1):35-43.
18. Serra-Majem L, Bassas L, García-Glosas R, Ribas L, Inglés C, Casals I, et al.
Cyclamate intake and cyclohexylamine excretion are not related to male
fertility in humans. Food Addit Contam. 2003; 20(12):1097-104.
Rev Assoc Med Bras 2016; 62(2):120-122